delta1, 4-17alpha, 20beta, 21-trihydroxy-3, 11-diketopregnadiene-derivatives



United States Patent 3,329,693 A -170,20fi,21-TRIHYDR0XY-3,11-DIKET0-PREGNADlENE-DERIVATIVES Stefan Antoni Szpilfogel and Max Salomon deWinter,

Oss, Netherlands, assignors to Organon, Inc., Orange, N. J., acorporation of New Jersey No Drawing. Filed Mar. 8, 1957, Ser. No.644,741 Claims priority, application Netherlands, Mar. 20, 1956, 205,5814 Claims. (Cl. 260397.45)

The invention relates to the preparation of new, biologically active,pregnane compounds, which have, in ring A, a double bond between theC-atoms 1-2 and 4-5, in 3-position a keto-group, in the positions 17,20, and 21 a hydroxyl group, and which can furthermore be substituted inthe nucleus by e.g. one or more free or functionally converted hydroxylor keto groups and by halogen and/or alkyl groups and in addition mayhave one or more other double bonds, and of functional derivatives ofthese compounds.

The preparation according to the invention occurs by reduction of the20-keto group of a non-, completely, or partially esterified A-17u,21-dihydroxy-3,ZO-diketo-pregnadiene compound which may furthermorebe substituted in the nucleus and may contain in addition one or moreother double bonds, to the 20/3-hydroxyl group by means of an alkalimetal borohydride or an alkali metal trialkoxyborohydride.

With the process according to the invention reduction of the 20-ketogroup of A -3,ZO-diketo-pregnadienes to the 20,8-hydroxyl group takesplace without the double bonds present and the 3-keto group need to beprotected, and a yield of more than 60% of the desired ZOB-hydroxyproducts is obtained in which neither the 12 double bond nor the 3-ketogroup is reduced.

The reduction takes place at temperatures ofbetween about 5 and +25 C.Preferably the reaction is carried out at about 0 C.

The reduction is carried out with an alkali metal borohydride, such aspotassium and sodiumborohydride, or with an alkali metaltrialkoxyborohydride, such as the sodium triethoxyborohydride. Theapplication of a somewhat more than equimolar quantity of the reducingagent has turned out to be very favourable.

As starting substances may serve A -3,20-diketo-17a, 2l-dihydroxypregnadienes, which may further be substituted in the skeleton by e.g.free or functionally converted hydroxyl or keto groups, e.g. in thepositions 6, 7, 11, 12, and 14 and/or by halogen atoms and/or alkylgroups e.g. in the positions 2, 6, 7, 8, 9, 11, 12, 14, and 16, and/ormay contain one or more other double bonds e.g. between the C-atoms 6-7,7-8, 89, 9-11, 11-12, and 14-15. The final products of the presentprocess are important for the cortisone-like activity. The preparationof the starting substances is disclosed in copending application Ser.No. 587,946, filed May 29, 1956, and is also disclosed in Belgian PatentNo. 548,288, granted on June 15, 1956.

As examples of starting products may be mentioned:

A -17og2 l-dihydroxy-3 ,11,20-triketo pregnadiene A 1 18,l7a,2l-trihydroxy-3,20-diketo pregnadiene;

A -9u-fiuoro-17a,2l-dihydroXy-3,11,20-triketo pregnadiene;

A -9u-chloro-1 1fl,17a,21-trihydroxy-3 ,20-diketo pregnadiene;

3,329,693 Patented July 4, 1967 A -17a,2l-dihydroxy-3,20-diketopregnatriene; A -11a,'l7a,21-trihydroxy-3,20-diketo pregnadiene, and

esters of these compounds.

The starting substances may e.g. be esterified with aliphaticcyclo-aliphatic, aromatic, or araliphatic carboxylic acids whether ornot substituted and having no more than 10 C-atoms, such e.g. as aceticacid, propionic acid, capronic acid, caprylic acid,cyclopentyl-propionic acid, cycyohexylbutyric acid, benzoic acid, andphenyl propionic acid.

The reduction of the 20-keto group according to the invention is carriedout in a suitable organic solvent or a mixture hereof with water. Assolvents may be used a lower aliphatic alcohol, such e.g. as methanol,ethanol, propanol, iso-propanol, and t-butanol, an ether, such e.g. asdimethyl ether, di-ethyl ether, methylethyl ether, or dioxane, ortetrahydrofurane, or a mixture of these solvents. Preferably methanol isused.

Under nitrogen atmosphere the reducing agent, e.g. NaBH dissolved in thesame solvent, is added to this solution. After stirring for some timethe reaction mixture is acidified, e.g. with glacial acetic acid, thenevaporated, and diluted with water. Subsequently the mixture isextracted with an organic liquid not mixable with water, such e.g. aschloroform, carbon tetrachloride, tetrachloro ethane, benzene, washedwith a dilute alkali hydroxide solution and then with water. The extractis subsequently dried and evaporated, after which the desired, ifnecessary completely or partially esterified, ZOIB-hydroxy-pregnadienecompound is obtained. This product can be crystallised from e.g.methanol, and then, if necessary, be saponified or esterified.

Example 1 1 g. of A-l7u,21-dihydroxy-3,ILZO-triketO-pregnadiene-ZI-acetate is dissolved in200 ml. of methanol. After cooling to 2 C. 143 mg. of NaBI-I dissolvedin 20 ml. of methanol, are added to this solution while stirring undernitrogen atmosphere. After stirring at 02 C. for 1 hour the reactionmixture is brought at pH 5.4 with glacial acetic acid, subsequentlyevaporated in vacuo to about 20 ml. and then diluted with 200 ml. ofwater. The solution is extracted with chloroform and the extract iswashed with icy-cold 1 N NaO-H and subsequently with Water. After dryingand evaporating the solvent, the crude A 17a,20 8,21-trihydroxy 3,11diketo-pregnadiene-Zl-acetate is obtained. crystallisation from methanolyields the pure substance with a M.P. of 228-230 C.; (a) 128 (indioxane).

Acetylation with acetic acid anhydride in pyridine yields the 20,21diacetate with the M.P. 239240 C.; (a) =+146 (in dioxane).

The saponification with 1.1 equivalent alkali in methanol solution andunder nitrogen atmosphere yields the free A -l7a,20,-3,2l-trihydroxy-3,ll-diketo pregnadiene with a M.P. of 180 C. and (a) =111 (in dioxane).

The reduction of A -17a,21-dihydroxy-3,11,20triketopregnadiene-Zl-acetate to the corresponding 20-hydroxy compoundhas also been performed by means of potassiumborohydride andsodiumtriethoxy-borohydride.

Example 2 1 g. of A -11fi,17a,2l-trihydroxy-3,20-diketo pregnadiene isdissolved in 200 m1. of methanol. At 0 C. ,a solu- Example 3 In the samemanner as given in the Examples 1 and 2, other A -3,20-diketo-17,21dihydroxy-pregnadienes including A 1704,21dihydroxy-3,l1,20-triketo-pregnatriene-Zl-propylate; A -11/3,17a,21trihydroxy-3,20-diketo-9wiluoro-pregnadiene-ZI-B-phenylpropionate;A17419 -17u,21-dihydroxy-3,ZO-diketo pregnatriene and A'17a,2l-dihydroxy-3,11,20-triketo 2 methyl-pregnadiene have been reducedto the corresponding ZO-hydroxy-compounds by means of sodiumborohydride,potassiurnborohydride and sodiumtriethoxyborohydride.

We claim:

1. A compound of the formula:

wherein R is selected from the group consisting of hydrogen and a methylgroup, R is selected from the group consisting of (H) (,BOH) and 0, R isfluorine, R is selected from the group consisting of hydrogen and anacyl group containing from 1 to carbon atoms, and

the bond between the carbon atoms 6 and 7 is selected from the groupconsisting of a saturated linkage and a double bond.

2. A -11B,17a,20fi,2l-tetrahydroXy-3-keto-9mfluoropregnadiene-Zl-,8-phenylpropionate.

4 3. A compound of the formula CI'IZOR H-C-OH wherein X is selected fromthe group consisting of hydrogen and fluorine, and R is selected fromthe group consisting of hydrogen and lower alkanoyl radicals.

4. A compound of the formula CH OR wherein R is the acyl radical of ahydrocarbon carboxylic acid containing up to 10 carbon atoms.

References Cited UNITED STATES PATENTS 2,773,888 12/1956 Oliveto et a1260-39745 2,776,927 1/1957 Shull 51 2,819,264 -l/1958 Gould et al260239.55 2,837,464 6/ 1958 Nobile 19551 2,852,538 9/1958 Scheri et a1260397.45

OTHER REFERENCES Recent Progress in Hormone Research, vol. 11, 1955.Szpilfogel et a1.: Rec. Trav. Chim., vol 75, pp. 1227- 32 (1956).

ELBERT L. ROBERTS, Primary Examiner.

JULIUS FROME, B. E. LANHAM, L. H. GASTON,

IRVING MARCUS, Examiners.

A. G. YARTZO'FF, B. G. COLLEY, G. E. LANDE,

Assistant Examiners.

1. A COMPOUND OF THE FORMULA: